Wednesday, September 17, 2025 9/17/2025

Dissecting the impact of RNA on DNA replication and chromatin structure

Award Number: R35GM134918
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

Group Awards By:

View Award Description

Dissecting the impact of RNA on DNA replication and chromatin structure - PROJECT SUMMARY Collisions between the DNA replication and transcription machineries (replication-transcription conflicts) appear to be common in eukaryotic cells. Although these conflicts have long been studied as a potential source of DNA damage and, therefore, a threat to genome integrity, we lack a detailed molecular understanding of how the presence of transcribing RNA polymerases on DNA affects the progress of replication, and of the mechanism(s) by which these replication-transcription conflicts give rise to DNA damage. Another consequence of transcription during DNA replication is elevated levels of ribonucleoside triphosphates (rNTPS) – the substrate for RNA polymerases. Due to incomplete discrimination between rNTPs and dNTPs by the replicative DNA polymerases, large numbers of ribonucleotides are mis-incorporated into the genome during each round of replication; this burden is estimated at > 1 million ribonucleotides per cell division in human cells, making ribonucleotides by far the most abundant lesion in eukaryotic DNA. Mis-incorporated ribonucleotides are removed via the ribonucleotide excision repair (RER) pathway, and impaired removal is linked to several human diseases. However, it is not known how ribonucleotides impact chromatin – the higher-order structure of DNA – or conversely how chromatin affects RER. Furthermore, it has not been determined whether all ribonucleotides are equally amenable to repair or what may underlie differences in RER efficiency through the genome. The proposed work encompasses two ongoing projects: The first project addresses how orientation-dependent effects on replication progression and genome integrity arise at transcribed genes. To achieve this, we use a recently developed quantitative method to assay the movement of the replisome genome-wide at high resolution, in combination with genome-wide interrogation of DNA double-strand break formation and a novel assay to map nascent DNA strands in the context of an arrested replication fork. The second project uses a combination of genome-wide assays and in vitro biochemistry to delineate how ribonucleotides destabilize nucleosomes (the basic repeating unit of chromatin), how nucleosomes affect RER initiation by the RNase H2 enzyme, and to elucidate the dynamics of RER at all loci in the genome. The machineries responsible for DNA replication, transcription, and DNA repair are highly conserved throughout eukaryotes. Both projects will be carried out in the budding yeast Saccharomyces cerevisiae: the small genome, rapid replication, and genetic manipulability of S. cerevisiae make this an ideal model in which to study the intersection of fundamental biological processes. Therefore, the results of this work will provide molecular insights into genome instability in humans, and will be directly applicable to our understanding of the etiology and progression of cancer as well as rare diseases including Aicardi-Goutières syndrome.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $642,390 )
2025	2025	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	6	4/16/2025	COMPETING CONTINUATION	$642,390
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	002	5	8/26/2025	NON-COMPETING CONTINUATION	$0
2025	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	5	11/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $642,390

Issue Date FY: 2024 ( Subtotal = $600,077 )
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	5	1/24/2024	NON-COMPETING CONTINUATION	$540,068
2024	2024	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	5	6/20/2024	NON-COMPETING CONTINUATION	$60,009
														Subtotal = $600,077

Issue Date FY: 2023 ( Subtotal = $600,077 )
2023	2023	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	4	2/16/2023	NON-COMPETING CONTINUATION	$600,077
														Subtotal = $600,077

Issue Date FY: 2022 ( Subtotal = $600,077 )
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	3	2/17/2022	NON-COMPETING CONTINUATION	$540,068
2022	2022	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	001	3	7/25/2022	NON-COMPETING CONTINUATION	$60,009
														Subtotal = $600,077

Issue Date FY: 2021 ( Subtotal = $600,077 )
2021	2021	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	2	2/18/2021	NON-COMPETING CONTINUATION	$600,077
														Subtotal = $600,077

Issue Date FY: 2020 ( Subtotal = $550,793 )
2020	2020	NEW YORK UNIVERSITY	70 WASHINGTON SQ S	NEW YORK	NY	10012	NEW YORK	USA	Biomedical Research and Research Training	000	1	1/23/2020	NEW	$550,793
														Subtotal = $550,793

Grand Total All Awards = $3,593,491

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Dissecting the impact of RNA on DNA replication and chromatin structure

Award Number: R35GM134918

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer